scholarly journals Association between cytokines and functional, hemodynamic parameters, and clinical outcomes in pulmonary arterial hypertension

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401879405 ◽  
Author(s):  
Aditya A. Joshi ◽  
Ryan Davey ◽  
Youlan Rao ◽  
Kai Shen ◽  
Raymond L. Benza ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Clinical Outcomes ◽  
Functional Class ◽  
Right Atrial ◽  
Walking Distance ◽  
Hemodynamic Parameters ◽  
Risk Of Death ◽  
Cytokine Levels ◽  
Pulmonary Arterial

To assess the relationship of cytokines with functional and clinical outcomes in pulmonary arterial hypertension (PAH). Endothelial dysfunction and vascular inflammation are characteristic of PAH. We investigated whether markers of angiogenesis and inflammation associated with functional, hemodynamic parameters, and clinical outcomes in PAH. PAH patients (n = 206) were pooled from two clinical trials: TRUST-1 and FREEDOM-C2. Baseline and post-treatment cytokine levels were correlated to baseline clinical and hemodynamic parameters, were assessed in clinical subgroups, and were associated with clinical outcomes. In 206 patients (mean age = 48 years; 74% women) with WHO group-1 PAH, most cytokine levels were higher in those with 6-min walking distance (6MWD) < median (335 m) vs. those above median, including Ang-1 (11.9 ± 10.1 vs. 5.9 ± 6.0 ng/mL), Ang-2 (14.3 ± 11.8 vs. 12.2 ± 11.2 ng/mL), and MMP-9 (221 ± 262.3 vs. 119 ± 171 ng/mL). Baseline 6MWD inversely correlated with Ang-1 (r = −0.27, P < 0.0001), Ang-2 (r = −0.20, P = 0.004), and MMP-9 (r = −0.27, P < 0.0001). MMP-9 levels differed significantly by NYHA functional class ( P = 0.001) suggesting an association between MMP-9 and subjective PAH severity. Mean Ang-2 levels were higher in those with baseline right atrial pressure (RAP) > 15 mmHg compared to those with RAP < 15 mmHg (23,841 vs. 11,020 pg/mL). Baseline RAP was associated with change in MMP-9 levels (r = −0.53, P = 0.03). Finally, baseline Ang-1, VEGF and MMP-9 levels were associated with risk of death and hospitalization at 16-week follow-up. Inflammatory cytokines and vascular angiogenesis markers are associated with baseline functional, hemodynamic parameters in PAH, and predict death and hospitalization. Larger prospective studies are needed to confirm the utility of cytokines in PAH.

scholarly journals Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension

2018 ◽  
Vol 51 (6) ◽  
pp. 1800467 ◽  
Author(s):  
Grayson L. Baird ◽  
Christine Archer-Chicko ◽  
R. Graham Barr ◽  
David A. Bluemke ◽  
Andrew E. Foderaro ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dehydroepiandrosterone Sulfate ◽  
Functional Class ◽  
Walking Distance ◽  
Risk Of Death ◽  
Menopausal Women ◽  
Hormonal Modulation ◽  
Pulmonary Arterial ◽  
Post Menopausal

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL−1) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5–2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.

scholarly journals First-in-child use of the oral selective prostacyclin IP receptor agonist selexipag in pulmonary arterial hypertension

2017 ◽  
Vol 7 (2) ◽  
pp. 551-554 ◽  
Author(s):  
Lianne M. Geerdink ◽  
Harald Bertram ◽  
Georg Hansmann
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Receptor Agonist ◽  
Diastolic Pressure ◽  
Functional Class ◽  
Right Atrial ◽  
Walking Distance ◽  
Off Label ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. Selexipag is a selective prostacyclin receptor agonist with vasodilatory, anti-proliferative, anti-inflammatory, and pro-angiogenic properties. However, no clinical data on its therapeutic use in children with PAH are currently available. Here, we report the case of a 12-year-old girl who presented in World Health Organization (WHO) functional class III and right ventricular (RV) failure with recurrent syncope, dizziness, and progressive fatigue for two years. Cardiac catheterization revealed severe precapillary PAH: mean right atrial pressure (RAP) = 10–13 mmHg, right ventricular end-diastolic pressure (RVEDP) = 13 mmHg, left ventricular end-diastolic pressure (LVEDP) = 7 mmHg, mean pulmonary arterial pressure (PAP) = 81 mmHg, and mean aorta ascendens pressure = 89 mmHg. The pulmonary vascular resistance index (PVRi) was 25.2 WU × m2. An oral combination therapy was started with a phosphodiesterase type 5 inhibitor (sildenafil 3 × 20 mg) and an endothelin-1 receptor antagonist (bosentan 2 × 62.5 mg). No significant clinical/hemodynamic improvement was seen after nine months of dual therapy, so that the patient was transferred to our institution. We agreed upon the off-label add-on use of oral selexipag. Within ten days, we up-titrated selexipag to a final (max. adult) dose of 1600 mcg twice daily. After six months, the patient had: (1) decrease in PVR index, pulmonary artery acceleration time, RAP, RVEDP, right atrial/RV size; (2) re-gain of vasoreactivity; and (3) improvement of cardiac index, 6-minute walking distance, functional class, body weight, and CAMPHOR score. Our encouraging results suggest the consideration of off-label use of oral selexipag in children with severe PAH, preferably in a protocol-driven prospective study.

Single-center prognostic validation of the risk assessment of the 2015 ESC/ERS guidelines in patients with pulmonary arterial hypertension in Japan

2020 ◽  
Vol 98 (9) ◽  
pp. 653-658 ◽  
Author(s):  
Ryo Imai ◽  
Shiro Adachi ◽  
Masahiro Yoshida ◽  
Shigetake Shimokata ◽  
Yoshihisa Nakano ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Pulmonary Arterial Hypertension ◽  
High Risk ◽  
Arterial Hypertension ◽  
Risk Group ◽  
Low Risk ◽  
World Health ◽  
Right Atrial ◽  
Walking Distance ◽  
Pulmonary Arterial

The 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension include a multidimensional risk assessment for patients with pulmonary arterial hypertension (PAH). However, prognostic validations of this risk assessment are limited, especially outside Europe. Here, we validated the risk assessment strategy in PAH patients in our institution in Japan. Eighty consecutive PAH patients who underwent right heart catheterization between November 2006 and December 2018 were analyzed. Patients were classified as low, intermediate, or high risk by using a simplified version of the risk assessment that included seven variables: World Health Organization functional class, 6-min walking distance, peak oxygen consumption, brain natriuretic peptide, right atrial pressure, mixed venous oxygen saturation, and cardiac index. The high-risk group showed significantly higher mortality than the low- or intermediate-risk group at baseline (P < 0.001 for both comparisons), and the mortalities in the intermediate- and low-risk groups were both low (P = 0.989). At follow-up, patients who improved to or maintained a low-risk status showed better survival than those who did not (P = 0.041). Our data suggest that this risk assessment can predict higher mortality risk and long-term survival in PAH patients in Japan.

scholarly journals Is hyponatremia associated with mortality in pulmonary arterial hypertension?

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401877688 ◽  
Author(s):  
Anastasiia A. Rudkovskaia ◽  
Adriano R. Tonelli ◽  
Youlan Rao ◽  
Jeffrey P. Hammel ◽  
Gregory K. Buller ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Sodium Level ◽  
Continuous Variable ◽  
Functional Class ◽  
Right Atrial ◽  
Left Heart Failure ◽  
Tertiary Referral Center ◽  
Pulmonary Arterial ◽  
One Year

Hyponatremia is associated with poor prognosis in left heart failure and liver disease. Its prognostic role in pulmonary arterial hypertension (PAH) is not well defined. We investigated the association between hyponatremia and one-year mortality in two large cohorts of PAH. This study is a secondary analysis evaluating the association between hyponatremia and one-year mortality in patients treated with subcutaneous treprostinil (cohort 1). The results are validated using a PAH registry at a tertiary referral center (cohort 2). Eight-hundred and twenty patients were enrolled in cohort 1 (mean age = 47 ± 14 years) and 791 in cohort 2 (mean age = 55 ± 15 years). Sodium level is negatively correlated with mean right atrial pressure (r = −0.09, P = 0.018; r = −0.089, P = 0.015 in cohorts 1 and 2, respectively). In unadjusted analyses of cohort 1, the sodium level (as a continuous variable) is associated with one-year mortality (hazard ratio = 0.94; P = 0.035). Hyponatremia loses its significance (as a continuous variable and when dichotomized at ≤ 137 mmol/L; P = 0.12) when adjusted for functional class (FC), which is identified as the variable whose presence turns the effect of sodium level into non-significant. Secondary analyses using a cut-off value of < 135 mmol/L showed similar results. These results are validated in cohort 2. Although the sample size for patients with sodium < 130 mmol/L is small (n = 31), severe hyponatremia is associated with higher overall mortality (47% versus 23%; P = 0.01), even when adjusting for age, FC, and baseline 6-min walk distance ( P < 0.001). Although baseline hyponatremia is associated with one-year mortality, it loses its significance when adjusted for FC.

scholarly journals Higher plasma fibroblast growth factor 23 levels are associated with a higher risk profile in pulmonary arterial hypertension

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401989544 ◽  
Author(s):  
Habib Bouzina ◽  
Roger Hesselstrand ◽  
Göran Rådegran
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Right Atrial ◽  
Walking Distance ◽  
Fibroblast Growth ◽  
Pulmonary Arterial ◽  
Metabolic Biomarkers

Metabolic abnormalities are proposed to contribute to pulmonary arterial as well as right ventricular remodelling in pulmonary arterial hypertension. Among the proposed abnormalities are altered glucose and lipid processing, mitochondrial malfunction, oxidative stress as well as vitamin D and iron abnormalities. In the present study, we investigated 11 metabolic plasma biomarkers, with the hypothesis that metabolic proteins may mirror disease severity in pulmonary arterial hypertension. Using proximity extension assays, plasma metabolic biomarkers were measured in 48 pulmonary arterial hypertension patients at diagnosis and, in 33 of them, at an early treatment follow-up, as well as in 16 healthy controls. Among the studied metabolic biomarkers, plasma fibroblast growth factor-23 ( p < 0.001), fibroblast growth factor-21 ( p < 0.001), fatty acid binding protein 4 ( p < 0.001) and lectin-like oxidised low-density lipoprotein receptor 1 ( p < 0.001) were increased and paraoxonase-3 was decreased ( p < 0.001) in pulmonary arterial hypertension at diagnosis versus controls. Fibroblast growth factor-23 showed the strongest correlations to studied clinical parameters and was therefore selected for further analyses. Fibroblast growth factor-23 correlated specifically to mean right atrial pressure ( r = 0.67, p < 0.001), six-min walking distance ( r = −0.66, p < 0.001), NT-proBNP ( r = 0.64, p < 0.001), venous oxygen saturation ( r = −0.61, p < 0.001), cardiac index ( r = −0.39, p < 0.007) and pulmonary vascular resistance ( r = 0.37, p < 0.01). Fibroblast growth factor-23 correlated moreover to ESC/ERS ( r = 0.72, p < 0.001) and the REVEAL risk score ( r = 0.61, p < 0.001). Comparing early treatment follow-up with baseline, fibroblast growth factor-23 decreased ( p < 0.02), with changes in fibroblast growth factor-23 correlating to changes in six-min walking distance ( r = −0.56, p < 0.003), venous oxygen saturation ( r = −0.46, p < 0.01), pulmonary vascular resistance ( r = 0.43, p < 0.02), mean right atrial pressure ( r = 0.38, p < 0.04) and cardiac index ( r = −0.39, p < 0.04). Elevated plasma fibroblast growth factor-23 levels at pulmonary arterial hypertension diagnosis were associated with worse haemodynamics and a higher risk profile, and were decreased after the administration of pulmonary arterial hypertension-specific treatment.

scholarly journals Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)

2015 ◽  
Vol 45 (5) ◽  
pp. 1303-1313 ◽  
Author(s):  
Lewis J. Rubin ◽  
Nazzareno Galiè ◽  
Friedrich Grimminger ◽  
Ekkehard Grünig ◽  
Marc Humbert ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Primary Objective ◽  
Functional Class ◽  
World Health ◽  
Walking Distance ◽  
Open Label ◽  
Pulmonary Arterial

Riociguat is a soluble, guanylate cyclase stimulator, approved for pulmonary arterial hypertension. In the 12-week PATENT-1 study, riociguat was well tolerated and improved several clinically relevant end-points in patients with pulmonary arterial hypertension who were treatment naïve or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 open-label extension evaluated the long-term safety and efficacy of riociguat.Eligible patients from the PATENT-1 study received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was to assess the safety and tolerability of riociguat; exploratory efficacy assessments included 6-min walking distance and World Health Organization (WHO) functional class.Overall, 396 patients entered the PATENT-2 study and 324 (82%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1, with cases of haemoptysis and pulmonary haemorrhage also being observed in PATENT-2. Improvements in the patients', 6-min walking distance and WHO functional class observed in PATENT-1 persisted for up to 1 year in PATENT-2. In the observed population at the 1-year time point, mean±sd 6-min walking distance had changed by 51±74 m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients versus the PATENT-1 baseline.Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional capacity for up to 1 year.

scholarly journals Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis

2017 ◽  
Vol 7 (2) ◽  
pp. 486-493 ◽  
Author(s):  
Kishan S. Parikh ◽  
Youlan Rao ◽  
Tariq Ahmad ◽  
Kai Shen ◽  
G. Michael Felker ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Patient Characteristics ◽  
Functional Class ◽  
Walking Distance ◽  
P Value ◽  
Novel Approach ◽  
Treatment Naïve ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. An unbiased cluster analysis was performed on 17 baseline clinical variables of PAH patients from the FREEDOM-M, FREEDOM-C, and FREEDOM-C2 randomized trials of oral treprostinil versus placebo. Participants were either treatment-naïve (FREEDOM-M) or on background therapy (FREEDOM-C, FREEDOM-C2). We tested for association of clusters with outcomes and interaction with respect to treatment. Primary outcome was 6-minute walking distance (6MWD) change. We included 966 participants with 12-week (FREEDOM-M) or 16-week (FREEDOM-C and FREEDOM-C2) follow-up. Four patient clusters were identified. Compared with Clusters 1 (n = 131) and 2 (n = 496), Clusters 3 (n = 246) and 4 (n = 93) patients were older, heavier, had worse baseline functional class, 6MWD, Borg Dyspnea Index, and fewer years since PAH diagnosis. Clusters also differed by PAH etiology and background therapies, but not gender or race. Mean treatment effect of oral treprostinil differed across Clusters 1–4 increased in a monotonic fashion (Cluster 1: 10.9 m; Cluster 2: 13.0 m; Cluster 3: 25.0 m; Cluster 4: 50.9 m; interaction P value = 0.048). We identified four distinct clusters of PAH patients based on common patient characteristics. Patients who were older, diagnosed with PAH for a shorter period, and had worse baseline symptoms and exercise capacity had the greatest response to oral treprostinil treatment.

L-arginine plasma levels and severity of idiopathic pulmonary arterial hypertension

VASA ◽  
2008 ◽  
Vol 37 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Beyer ◽  
Kolditz ◽  
Ewert ◽  
Rubens ◽  
Opitz ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Plasma Levels ◽  
High Performance ◽  
Functional Class ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Right Atrial ◽  
Heart Catheterization ◽  
Pulmonary Arterial ◽  
Minute Walk

Background: Idiopathic pulmonary arterial hypertension (iPAH) is a rare disease of unknown aetiology characterized by a poor prognosis. Impairment of nitric oxide (NO) synthesis or NO-induced vasorelaxation has been suspected to play a role in the development of iPAH. This study was performed to investigate possible correlations between the plasma levels of the NO-related aminoacids L-arginine, L-citrulline and N-hydroxy-L-arginine (L-NHA) and the severity of iPAH. Methods: In twelve iPAH patients hemodynamics were measured by right heart catheterization, and plasma levels of L-arginine, L-citrulline and L-NHA were determined in blood samples from the pulmonary artery, peripheral artery and peripheral vein by high-performance liquid chromatography analysis. In eight of twelve patients a six minute walk test was performed. Results: Plasma levels of L-arginine strongly correlated to right atrial pressure, cardiac output, cardiac index, mixed-venous oxygen saturation, six minute walk data and NYHA functional class at all sites of blood sampling (p < 0.05). Conclusions: The results suggest a possible role of the NO precursor L-arginine in the pathogenesis of iPAH.

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